A comprehensive review of oral microenvironment changes and orofacial adverse reactions after COVID‐19 vaccination: The good, the bad, and the ugly

Abstract Background and Aims Anti‐severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) vaccines have the potential to alter several biological systems concurrently with remolding the immune system, most of which are related to immunization, while some others are known as adverse effects. This review aims to explore the potential effects of vaccination on the oral microenvironment and classifies them as good, bad, or ugly, with a brief review of facial diseases following coronavirus disease 2019 (COVID‐19) vaccination. Methods This study was a comprehensive review conducted through searching related articles in Medline, Scopus, and Google Scholar databases. Results On one side, the “Good” impacts of vaccination on the oro‐nasal mucosa are explained as if the mucosal immune responses followed by SARS‐CoV‐2 vaccines are enough to provide immunity. On the other side, the possible “Bad” and “Ugly” effects of the vaccine, which manifest as orofacial adverse events and autoimmune reactivations, respectively, should be noted. Exacerbation of pre‐existing autoimmune conditions such as lichen planus, pemphigus vulgaris, bullous pemphigoid, and Stevens‐Johnson syndrome have been reported. Conclusion COVID‐19 vaccines could affect different biological systems alongside stimulating the immune system, and some of these effects are referred to as adverse effects. Nonetheless, these adverse effects are treatable, and healthcare professionals should not prevent patients from taking the first available vaccination.


| The mucosal immune system response to SARS-CoV-2 infection
Even though the COVID-19 pandemic has been ongoing for years, the role of mucosal immunity in SARS-CoV-2 infection has attracted little attention.The mucosal immune system is the greatest component of the whole immune system in terms of immune cell recruitment and immunoglobulin secretion. 202][23] B cells incorporated in such mucosal inductive site tissues would either be differentiated into IgAsecreting plasma cells to produce polymeric IgA (pIgA), which then release as secretory IgA (SIgA), or systemic IgG-producing B cells to secrete circulating IgG. 24,25The main structural protein of the SARS-CoV-2 virus to enter the target cell, is the S protein; which is made up of S1 and S2 subunits.S1 subunit has a receptor binding domain (RBD) which provides viral attachment to ACE-2 receptor of the human cell and an S1 domain. 26The RBD and S1 domain have the most immunogenicity and are targeted by humoral or cellular immune system. 27

| The role of IgA
In response to SARS-CoV-2 infection, in mucosal inductive site tissues such as nasopharynx-associated lymphoid tissue (NALT). 28or even sublingual sites in the oral cavity, 23 IgA-producing mucosal B cells migrate and develop into IgA-secreting plasma cells. 24IgA antibodies against SARS-CoV-2 have been reported to be elevated in the nasal secretions and saliva of infected individuals.These findings support the notion that SARS-CoV-2 induces mucosal IgA antibody response.
Therefore, plasma IgA is suggested to be used as a diagnostic tool for the detection of infection. 29,30IgA consists of three molecular forms (secretory, monomeric, and polymeric) with two subclasses (IgA1 and IgA2). 31Surprisingly, salivary IgA is weakly matched with serum antibody levels which is partly attributable to the cross-reactive IgA produced by exposure to viruses other than SARS-CoV-2. 32Levels of IgA may also represent the degree of disease severity, as IgA production has been reported to be higher in severe patients compared to moderate or asymptomatic individuals. 33A, secreted by local plasma cells against RBD on the virus's spike protein, potentially neutralizes SARS-CoV-2 before it binds to epithelial cells. 34SIgA, the most abundant immunoglobulin secreted by mucosal surfaces, has a dimeric structure and comprises variable proportions of IgA1 and IgA2 subclasses.While circulating IgA is primarily monomeric and dominated by IgA1 subclass. 35The mucosal immune system creates an SIgA-dominated environment against viruses in the nasopharynx and the upper respiratory tract and bronchi, which is noninflammatory.However, the terminal airways and alveoli are mostly dominated by circulation-derived IgG. 7Since circulating monomeric IgA cannot be readily conveyed to mucosal secretions, there will likely be separate systemic and mucosal responses against this infection. 36

| Plasma and oral fluids antibody levels following vaccine administration
Plasma IgG and IgA levels have been observed to be elevated for up to 2 months after administration of the first dose of BNT162b2 vaccine, and after two doses of mRNA vaccines (ChAdOx1 nCoV-19 or BNT162b2 COVID-19). 37Additionally, increased levels of circulating IgM and IgG against S and RBD of SARS-CoV-2 were measurable for up to 8 weeks after the booster dose. 38Nevertheless, it is commonly assumed that intramuscular or subcutaneous vaccinations do not efficiently generate mucosal immunity compared to inhalable vaccines. 39Chan et al. 38 implied that BNT162b2 (but not Sinovac) increases levels of IgA and IgG antibodies with neutralizing activity in the nasal mucosa alongside the humoral immune system, and hypothesized that this increase reduces the asymptomatic transmission risk of virus.Saliva has been demonstrated to be a reliable biofluid for detecting the presence of SARS-CoV-2 mRNA. 40,41and also the salivary glands have been proposed to be as a viral reservoir. 42spite virus replication in the oral cavity, few studies have evaluated anti-SARS-CoV-2 antibodies produced by the oral mucosa or salivary glands.According to a study, mRNA vaccination produces measurable amounts of salivary S1-RBD IgA and IgG, but the ability to neutralize viral infection remained unclear. 43Another research demonstrated that plasma and saliva IgG antibodies against SARS-CoV-2 are retained for at least 3 months in the majority of COVID-19 patients.Based on this correlation between serum and saliva IgG, levels of salivary IgG antibody could be used as an indicator of systemic SARS-CoV-2 immunity maintenance. 29Additionally, IgA and IgM levels in response to spike and RBD antigens decrease significantly after 3 months, suggesting the fact that IgA levels remain elevated for a short period of time, which neither have diagnostic nor protective value in the long term. 29ngival crevicular fluid (GCF) is a highly concentrated serum effusion that drips into the gingival sulcus and includes critical substances and cells related to the immune system such as antibodies. 44Shedding of viruses like the human cytomegalovirus and the herpes simplex virus have been reported in the GCF. 45The SARS-CoV-2 RNA has been detected in both GCF and saliva with a sensitivity of 63.64% and 64.52% in comparison with nasopharyngeal swab sampling, respectively. 46Recently, it has been found that the rate of antibodies in GCF and plasma of COVID-19-positive patients is almost the same.This supports the notion that GCF could be used as a noninvasive method for monitoring the immune system status. 47tibody levels against S1-RBD antigen following the second dose of the mRNA BNT162b2 vaccine were significantly higher in GCF than saliva at every stage, and maximum levels were reached 3 weeks following vaccination. 48

| Mucosal vaccine delivery
It has been demonstrated that vaccines administered by injection are unable to effectively prevent viral infection at mucosal sites, such as the nasopharynx, and do not induce protective oral or nasal mucosal immunity via blocking virus transmission. 9Various mucosal noninvasive vaccines have developed (Table 1) to address these issues by stimulating long-lasting protective immune responses in the mucosal sites where SARS-COV-2 infection first enters. 49The majority of the COVID-19 mucosal vaccines under study are intended for intranasal administration.There are now a number of intranasal vaccines that are being tested both in preclinical and clinical settings. 50The SARS-COV-2 synthetic live attenuated vaccine, COVI-VAC, is administered intranasal.In contrast to other vaccines, COVI-VAC protects against all viral antigens, not only spike protein which is likely to be protective against a variety of SARS-CoV-2 strains. 51AdCOVID is an intranasal adenovirus type 5-vectored vaccine that encodes the SARS-CoV-2 spike protein's RBD.A single intranasal vaccination with AdCOVID resulted in a significant and targeted immune response against RBD through the secretion of mucosal IgA in the respiratory tract, as well as systemic immunity, which lasted for over 6 months. 52u et al. 53 developed a bacteriophage T4-based mucosal vaccine.It was demonstrated that intranasal administration of two doses of this vaccine, 21 days apart, provided both mucosal and systemic immunity. 53Additionally, oral vaccines have proven to successfully induce and activate the mucosal immune system for infectious diseases other than COVID-19. 54e tablet version of the vaccine would allow those without access to a vaccination site in underdeveloped countries to be vaccinated without a healthcare provider.Also, it reduces the risk of injectable vaccine's adverse effects, including malaise, discomfort, and inflammation. 63As an example, Vaxart is an enteric-coated tablet vaccine that induces more antiviral SARS-CoV-2-specific T cells, notably IFNg-producing CD8s, than conventional COVID-19 mRNA vaccines. 61gure 1.provides a summary of immune mechanisms and a comparison of mucosal vaccine delivery versus injectable vaccines.

| THE BAD
The post-COVID-19 vaccination symptoms resemble the post-COVID-19 infection condition in many ways.Fatigue has been the most prevalent complaint.More serious complications, including stroke, renal failure, myocarditis, and lung fibrosis have also been reported. 64Symptoms more related to the oral cavity have also been T A B L E 1 A summary of intranasal and oral vaccines.recorded, such as oral lesions, mucositis, petechiae, oral mucosal paresthesia or hypoesthesia, candida infection, and necrotizing gingivitis. 12,65The exact underlying mechanisms behind such oral manifestations have yet remained to be thoroughly explained.
However, some studies suggest the potential of direct SARS-CoV-2 invasion of oral keratinocytes, fibroblasts, tongue, and salivary gland epithelial cells as the etiopathogenic mechanism underlying SARS-CoV-2 oral adverse effects. 66Furthermore, there is growing evidence that anti-SARS-CoV-2 vaccines are related to orofacial side effects. 67 is noteworthy to mention that there are discrepancies in the descriptions of vaccine-related orofacial adverse events between the countries.There is a possibility that oral adverse reactions have been probably underreported by healthcare workers. 68However, the overall incidence rate of oral side effects following the anti-SARS-CoV-2 vaccines administration has been reported in a study conducted by Mazur et al. 69 to be rare with an overall incidence The immune mechanisms involved in mucosal immunity following coronavirus disease 2019 vaccination (comparing oral and nasal with injectable vaccines).rate of 3.1% and 5.4% after the first and second doses of BNT162b2 vaccine, respectively.

| Oral lesions
The majority of the vaccine-related oral lesions are commonly associated with or secondary to dermatological signs, thus, known as mucocutaneous adverse drug reactions. 69Erosion and ulcers have been the most common primary oral lesions observed in adult cases who received the anti-SARS-CoV-2 vaccine, similar to SARS-CoV-2positive patients.Nevertheless, erythema multiforme and erosiveulcerative lesions are mostly attributed to vaccine ADRs, despite aphthous-like and herpetiform lesions that are considered to be post-SARS-CoV-2 infection complications. 70higher occurrence of oral lesions after receiving anti-SARS-CoV-2 vaccines has been reported in females (68.8%) in comparison to males (31.2%).This is similar to the cutaneous reactions described after the BNT162b2 and mRNA-1273 vaccinations, which were nine times higher in female subjects.70,71 Even after receiving other antiviral vaccines such as anti-influenza, anti-Yellow Fever, and antirubella, the incidence of ADRs in females has been found to be higher than in males.72 In terms of vaccine type, the BNT162b2 vaccine has had a greater prevalence of cases reported with oral lesions, mostly in the form of erosions and ulcers.70 Yet this can be explained by the higher number of BNT162b2 doses delivered in Europe compared with other vaccines.73 Oral aphthous-like lesions have occurred after receiving the first (1.6% of cases) or the second dose (2.7% of cases).69 The mRNA-1273 vaccine is mostly associated with oral lesions in the form of erosions and ulcers similar to BNT162b2, but DNA-based viral vector vaccines such as ChAdOx1 and Ad26.-COV2.S (Janssen) are commonly attributed to oral lesions in the forms of maculae and white plaques, respectively.70 Few studies reported the adverse effects of BBIBP-CorV (Sinopharm) vaccine, which does not necessarily mean that this vaccine causes fewer complications.

| Oral mucositis
Oral mucositis can be either be triggered by a direct viral infection of the epithelial cells or induction of immune responses, followed by virus infection or vaccine administration. 74,75SARS-CoV-2 vaccination provokes a specific adaptive immune response which may underlie the mucosal hypersensitivity, as it has been shown that AZD1222 vaccine induces a T-cell-specific response. 75,76rthermore, immune cross-reactivity may result from similarities between some vaccine components (adjuvants) and human proteins, such as antigens expressed on keratinocytes. 77Additionally, it is probable that direct infection of cells expressing angiotensin I converting enzyme 2 receptor (such as epithelial cells of the tongue and salivary glands) by the attenuated or viral vector and rarely mRNA-based vaccines have contributed to the oral mucositis and ulcerations. 78,79

| Bell's palsy
Facial nerve palsy has also been described as a side effect of vaccine administration, most commonly after the influenza vaccine. 80The mRNA-based vaccines such as BNT162b2 and mRNA-1273 have been associated with a considerably greater incidence of Bell's Palsy than the Ad26.COV2.S COVID-19 vaccine. 81However, FDA noted that the incidence of Bell's palsy following COVID-19 vaccination did not exceed that of the general population and refuted a causal relationship between the vaccine delivery and the occurrence of Bell's palsy. 82,83

| Other adverse reactions
The burning sensation occurred as the most common oral adverse effect following both the first and second doses of BNT162b2 vaccine.Additionally, taste alterations frequently occurred after the second dose (3.4%), compared to the first dose (1.1%). 69The mRNA-1273 vaccine has caused rare orofacial ADRs, such as facial swelling in cases with previous cosmetic filler injections in the face or lips. 70reover, an unusual case of vaccine-related painful glossitis and xerostomia were recorded following administration of BNT162b2 vaccine which caused further stomatitis and tongue fissures.The symptoms resolved after 2 weeks of applying topical prednisolone. 84e allergic reactions might also be induced by ingredients of the vaccine, such as polysorbate 80 and polyethylene glycol (PEG), which makes skin or intradermal injection testing mandatory before administration. 85The allergic reaction could also lead to swollen lips, tongue, and mouth. 86,87summary of orofacial adverse reactions following COVID-19 vaccines is available in Table 2.

| THE UGLY
Recent studies have reported some cases of emergence or exacerbation of autoimmune diseases with symptoms in the oral region after COVID-19 vaccination.Oral lesions following anti-SARS-CoV-2 vaccinations can be classified as primary oral lesions or immunerelated exacerbation of autoimmune disease, of which the former has been discussed as the bad aspect and the latter will be reviewed below as the ugly consequences (a summary is provided in Table 3).

| Oral lichen planus
Oral lichen planus (OLP) is a chronic inflammatory condition that affects oral mucous membranes by inducing T-cell-mediated apoptosis of basal mucosal keratinocytes. 103COVID-19 vaccines have been linked in recent publications to be attributable to either the new onset or worsening of OLP.Evidence suggests that T-cellmediated immunity may be boosted by both mRNA and viral vector vaccinations. 104BNT162b2 vaccine has been shown to stimulate a strong CD8+ and T helper type 1 (Th1) cell response, as well as rising blood levels of IFN-γ, TNF-α, and IL-2. 105Upregulation of Th1 cells and elevation of pre-apoptotic cytokines, including IFN-γ and TNF-α have been reported as major agents responsible for the apoptosis of mucosal keratinocytes causing this autoimmune condition. 106It has been shown that the immune response to the Ad26.COV2.S vaccination remains for a longer time and has the potential to trigger autoimmunity. 107e study investigated potential risk factors for the development of oral lichen planus following immunization with mRNA-based vaccines. 108Serologically positive patients receiving the first dose of BNT162b2 had 140 times higher IgG titers than their maximal prevaccine levels.Moreover, persons have higher levels of antibody and T-cell response potency. 109It has been suggested for those with a previous record of COVID-19 infection that only a single dose of the BNT162b2 is recommended and would be sufficient to elicit a beneficial protective response with the lowest risk for incidence of adverse effects. 110

| Pemphigus vulgaris and bullous pemphigoid
Pemphigus vulgaris (PV) is a rare autoimmune disease that is characterized by painful blisters and erosions on the skin and mucous membranes.PV is thought to be a Th-dominant disease with the contribution of CD8 + T cells via Fas/FasL signaling pathway. 111Two theories may explain how vaccination causes or triggers relapses of PV: The first suggests that some cases are genetically susceptible to hyper-immunity.Another implies that vaccine antigens may crossreact with antigens associated with PV pathogenesis. 112Receiving a second dose of mRNA-based vaccines after the occurrence of autoimmune side effects following the first dose may be associated with the risk of worsening the condition, and administration of an alternative vaccine is highly recommended. 100llous pemphigoid (BP) is the most prevalent autoimmune subepidermal illness of the skin causing blisters, and it is sporadically accompanied by oral lesions. 113There have been cases reported with BP following the administration of SARS-CoV-2 mRNA-based vaccines. 114Those who have an immunological predisposition or subclinical BP may be more susceptible to developing an autoimmune reaction after vaccination. 115,116

| Stevens-Johnson syndrome
Stevens-Johnson syndrome (SJS) is an uncommon acute hypersensitivity immune reaction typically induced by medications causing severe necrosis of the skin and mucosal membranes.SJS is caused by a cytotoxic immunological response in keratinocytes that culminates in extensive keratinocyte apoptotic cell death. 117Although SJS is rarely associated with vaccinations, but second exposure to the causative agent leads to a recurrence that is typically more severe than the initial attack and may be fatal. 118Healthcare providers should be informed of this rare but severe condition to avoid receiving another dose of vaccine from the same type.

| Oral manifestations of thrombocytopenia
Immune thrombocytopenia (ITP) is a type of autoimmune-mediated reaction against platelets that can lead to a decrease in platelet count up to < 100 × 10 9 /L and subsequent submucosal bleeding with clinical manifestations of petechiae, purpura, excessive bruising, and bleeding. 119ITP can emerge secondary to COVID-19 infection or even during postrecovery period, due to immune system dysregulation, and is managed by glucocorticoids and intravenous immunoglobulin treatment. 119Palatal petechiae have been reported in a case as an uncommon oral adverse effect of ChAdOx1 vaccine administration concomitant with a temporary reduction in platelet count to • Oral mucositis 75 • Palatal petechial lesions 88 • Maculae 70 Janssen (Ad26.COV2.S) • Autoimmunologic reaction 89 • Mucocutaneous adverse reaction 90 • White plaques 70 Attenuated or inactivated virus Sinopharm (BBIBP-CorV) -Autoimmunologic reaction. 91rythema multiforme 92

Immune response following viral infection has been largely
studied as a triggering factor for the occurrence of autoimmune diseases. 121However, there is controversies regarding the same positive correlation to be found between various viral vaccinations and autoimmune responses.This notion is reported to be rare but possible, and susceptible patients with previous history of autoimmune diseases or having adverse reactions to other types of vaccines should be carefully assessed before viral vaccine administration. 122ccines against viral infections other than SARS-CoV-2 may also come with adverse effects with manifestations in the oral cavity.
Similar to the anti-SARS-CoV-2 vaccines, which have been widely administered after the outbreak, influenza vaccines are being received yearly, specifically by patients with systemic diseases. 123e results of a cohort study reported that there is no correlation between oral adverse effects and the administration of influenza vaccines. 124Nevertheless, some rare cases of autoimmunity have been reported for influenza vaccines.The cases appeared to be fewer than reported for anti-SARS-CoV-2 vaccines. 112Lichen planus following hepatitis B vaccination might also be accompanied by oral mucosa involvement, specifically lips, buccal mucosa, or dorsal part of the tongue. 125HBsAg is assumed to have a causative role in this process due to the fact that surface epitopes on keratinocytes are similar or even identical to protein S of the hepatitis B virus as a vaccine component.This similarity consequently results in T-cell activation and further immune responses to the mucosal cells. 126chenoid reaction is also reported in a few cases with the same involvement of protein S as an underlying mechanism.vaccinations are mainly limited to case studies with few reported cases.There is a need for studies in large-scale setting with higher levels of evidence.Given the novelty of research in this field, the correct frequency of each side effect remains unclear.Also, this study was a narrative review and does not follow a systematic approach.
Therefore, the risk of selection bias should be considered.

| CONCLUSION
COVID-19 vaccination, though promising for infection prevention, are not without side effects.However, the advantages outweigh the disadvantages, From a positive view, the vaccination can induce mucosal immunity.However, it is unclear whether this level of antibody produced by mucosa is protective.As IgA detected in saliva is primarily a product of mucosal immune response, more potent vaccines must be used to stimulate mucosal immunity to bring it up to protective levels.It is worth bearing in mind that mRNA-based vaccines that induce a more robust mucosal immune response and SIgA secretion are associated with a higher risk of mucosal hypersensitivity and autoimmunity.Additionally, injectable vaccines raise concerns regarding the long-term durability and efficiency of the mucosal immune response following vaccination, which is essential for inhibiting viral entrance through respiratory tracts.
Several oral/nasal-delivered mucosal vaccines have been proven to be effective in preventing respiratory infectious diseases such as COVID-19.More research is needed to determine the effectiveness and possible side effects of these vaccines in human studies.
From a negative view, vaccination may cause oral lesions and inflammation as well as temporarily worsening pre-existing disorders.
Nevertheless, these side effects are manageable, and healthcare providers should not discourage patients from receiving the first vaccine in access.To the best of our knowledge, there is no established guideline for scheduling or discontinuing COVID-19 vaccination for vulnerable cases.Therefore, the administration of another effective vaccine could be an appropriate decision, though we recommend further studies in this field to reach a consensus.

• Glossitis and Xerostomia 84 • 15 T A B L E 3 -
Erosions Summary of recent studies reporting cases of emergence or exacerbation of autoimmune diseases with oral lesions after COVID-19 vaccination.Oral lichen planus New onset 6 days after vaccination Oral mucosal discomfort, Aryanian et al.
T A B L E 2 Common and rare orofacial adverse effects following different types of COVID-19 vaccines.
Our research was critical for several reasons.It explored the scarcely examined territory of oral complications following COVID-19 vaccination.Although these adverse effects are rare, they are of paramount importance given the vast numbers of vaccinated individuals globally.Autoimmune reactions and reactivations postvaccination is a critical area given the emerging reports following vaccine administration.By investigating these under-researched facets, our study not only aims to bridge crucial knowledge gaps but also to provide pivotal insights for dentists and experts in this area.Some limitations should be considered for this study.First and foremost, the studies on oral side effects COVID-19 130,13128][129]ITP is among other possible Hepatitis B vaccine-related adverse reactions that mostly require no therapeutic interventions.130,131Measles, T A B LE 3 (Continued)